Enantiomer-enriched alpha-,omega-amino alcohol derivatives, their production and use as insect- and mite-repelling agents

ABSTRACT

The invention relates to an insect- and mite-repelling agent, characterized by a content of at least one substituted, enantiomer-enriched α-,ω-amino alcohol derivative of formula (1) wherein X represents hydrogen, COR 11  or R 13 , R 13  represents C 1 -C 6  alkyl, R 1  represents C 1 -C 7  alkyl, C 3 -C 7 alkenyl or C 2 -C 7  alkinyl, R 2  R 11 , R 13  are identical or different and represent C 1 -C 6  alkyl or C 2 -C 7  alkenyl, R 3 -R 8  are identical or different and represent hydrogen or C 1 -C 6  alkyl, wherein R 2  and R 3  or R 3  and R 7  or R 3  and R 5  or R 5  and R 7  can also form, together with the atoms to which they are bonded, a 5- or 6-membered monocycle ring. Also disclosed is a method for producing said agent.

The present invention relates to the preparation and use ofenantiomerically enriched substituted α,ω-amino alcohol derivatives asinsect and mite repellents. The present invention further provides novelsubstituted α,ω-amino alcohol derivatives.

Insect or mite repellents have the task of preventing harmful orannoying arthropods from touching, and also from stinging and sucking orbiting, on surfaces which attract them, for instance on the skin ofanimals and humans when they have been treated beforehand with suchrepellents.

Numerous active ingredients have already been proposed as repellents(cf., for example, K. H. Büchel in Chemie der Pflanzenschutz- undSchädlingsbekämpfungsmittel; [Chemistry of Crop Protectants andPesticides]; editor: R. Wegler, vol. 1, Springer Verlag Berlin,Heidelberg, New York, 1970, p. 487 ff.).

Particularly well known examples which have been in use for sometime areN,N-diethyl-3-methylbenzamide (DEET), dimethyl phthalate and2-ethylhexane-1,3-diol, of which DEET in particular has gainedconsiderable significance in practice (see, for example, R. K. Kocker,R. S. Dixit, C. I. Somaya; Indian J. Med. Res. 62,1 (1974)).

A considerable disadvantage of the known repellents is their sometimesrelatively short-lived duration of action (only a few hours).

Some of the compounds defined by the formula (1) which follows are knownin the form of racemates thereof (on this subject, see DE 1 288 587,column 2, formula 1 with the definition of R=methyl). This is anintermediate for the preparation of ethylN-(3-carbamoyloxyalkyl)carbamate, which is used as a sedative medicament(on this subject, see EP 0 144 825 A1, compound No. 37 on page 43),which serves as an intermediate for the preparation of antibioticcompounds.

DE-A 1 150 973 likewise discloses some compounds of analogous structure,which are used as medicaments.

However, no insect- and mite-repellent action of these compounds hasbecome known to date.

Substituted α,ω-amino alcohol derivatives of the formula (1) are alsoknown in the form of their racemic mixture of the individualenantiomers, as obtained in the chemical synthesis (EP A 289 842),

in which

-   -   X is hydrogen, COR¹¹ or R¹³, where R¹³ is C₁-C₆-alkyl,    -   R¹ is branched or linear C₁-C₇-alkyl, C₃-C₇-alkenyl or        C₂-C₇-alkynyl,    -   R² is C₁-C₆-alkyl or C₂-C₇-alkenyl,    -   R³ to R⁸ are the same or different and are each hydrogen or        C₁-C₆-alkyl, where R² and R³ or R³ and R⁷ or R³ and R⁵ or R⁵ and        R⁷, together with the atoms to which they are bonded, may also        form a 5- or 6-membered monocyclic ring.

It was an object of the invention to provide a more effective insect andmite repellent.

It has now been found that the individual optical isomers of these aminoalcohols of the formula 1 have different action as insect and miterepellents.

Even in the form of the racemic isomer mixtures used, these exhibit astrong insect- and mite-repellent action.

As in the case of all substances which occur in optical isomers, thebiological action of the individual enantiomers may be quite different,such that it appears to be advantageous to prepare the individualoptical isomers and to check their biological activity.

The most effective isomer can then be prepared in enriched orenantiomerically enriched faun and be marketed as a more effectiveinsect and mite repellent. The advantage of this procedure is asignificant reduction in the amount employed and “omission” of the lesseffective or ineffective isomers. In addition to an increase in theefficiency over the enantiomer mixtures, this prevents ineffectiveisomers burdened with possibly greater undesired side effects from beingemployed.

The invention therefore provides an insect and mite repellent,characterized by a content of at least one substituted enantiomericallyenriched α,ω-amino alcohol derivative of the formula (1)

in which

-   -   X is hydrogen, COR¹¹ or R¹³, where R¹³ is C₁-C₆-alkyl,    -   R¹ is C₁-C₇-alkyl, C₃-C₇-alkenyl or C₂-C₇-alkynyl,    -   R², R¹¹, R¹³ are the same or different and are each C₁-C₆-alkyl        or C₂-C₇-alkenyl,    -   R³ to R⁸ are the same or different and are each hydrogen or        C₁-C₆-alkyl, where R² and R³ or R³ and R⁷ or R³ and R⁵ or R⁵ and        R⁷, together with the atoms to which they are bonded, may also        form a 5- or 6-membered monocyclic ring.

The compounds of the general formula (1) can be prepared in analogy tothe racemic mixtures by known methods and processes (cf., for example,C. Ferri, Reaktionen der organischen Synthese [Reactions in OrganicSynthesis], Georg Thieme Verlag Stuttgart, 1978, p. 211 ff. and 496,497).

Accordingly, the compounds of the formula (1) are obtained when theoptically active α,ω-amino alcohols preparable by known processes (e.g.(S)- or (R)-2-(2-hydroxyethyl)piperidine→S. M. Kupchun et al. J. Am.Chem. Soc. 82 (1960) 2616) of the formula (2)

in which

-   -   R² to R⁸ are each defined as specified in formula (1)

are first reacted with chlorocarbonic esters, known per se, of theformula (3) in which R¹ is an optically active radical, for example (R)-or (S)-sec-butyl

and is otherwise defined as specified in the formula (1), optionally inthe presence of an acid acceptor, for example triethylamine or potassiumcarbonate, and optionally using a diluent, for example toluene, CH₂Cl₂,tetrahydrofuran or acetonitrile, at temperatures between −40 and 110° C.

In the case that R² and R³ together with the atoms to which they arebonded can form a 6-membered ring (piperidine), the chiral amino alcoholof the formula (2) can be prepared by a novel method by chiral ringhydrogenation of a corresponding pyridine (WO 2005/049570).

For the preparation of compounds of the general formula (1) in which Xis other than hydrogen, in a second reaction step, optionally afterisolation of the intermediate with a free OH group, the furtheracylation/alkylation is effected with carbonyl chlorides, known per se,of the formula (4)

R¹¹COCl   (4)

to prepare compounds of the formula (1) where X═COR¹¹;

or alkyl halides of the formula (6)

R¹³—Y   (6)

to prepare compounds of the formula (1) where X═R¹³;

where, in the formulae (4), (6), Y is chlorine, bromine or iodine,preferably bromine or iodine, and R¹¹ and R¹³ are each as defined above,

optionally in the presence of an acid acceptor, for exampletriethylamine or potassium carbonate, or of a base such as sodiumhydride or butyllithium, optionally using a diluent, for exampletoluene, tetrahydrofuran or acetonitrile, at temperatures between −78and 110° C.,

b) the compounds of the formula (1) are also obtained when the α,ω-aminoalcohols or α,ω-amino ethers, known per se or preparable by knownprocesses, of the formula (10)

in which

R³ to R⁸ are each defined as specified in formula (1) and where X′ ishydrogen or R¹³, are first reacted with chlorocarbonic esters, known perse, with an optically active alkyl radical R¹ of the formula (3),optionally in the presence of an acid acceptor, for exampletriethylamine or potassium carbonate, or optionally using a diluent, forexample toluene, CH₂Cl₂, tetrahydrofuran or acetonitrile, attemperatures between −40 and 110° C.

In a second reaction step, for the preparation of compounds of theformula (1) in which X is not R¹³ or hydrogen, optionally afterisolation of the intermediate with a free OH group, the furtheracylation is then carried out with carbonyl chlorides, known per se, ofthe formula (4) to prepare compounds of the formula (1) where X═COR¹¹,where R¹¹ in the formula (4) is defined as specified above, optionallyin the presence of an acid acceptor, for example triethylamine orpotassium carbonate, or optionally using a diluent, for example toluene,tetrahydrofuran or acetonitrile, at temperatures between −78 and 110° C.In a third reaction step, optionally after isolation of the intermediatewith a free NH group, the further N-alkylation is then carried out withalkyl halides of the formula (11)

R²—Y′  (11)

to prepare compounds of the formula (1) in which Y′ is chlorine, bromineor iodine, preferably bromine or iodine, and R² is defined as specifiedabove, optionally in the presence of a base, for example sodium hydrideor butyllithium, optionally using a diluent, for example toluene ortetrahydrofuran, at temperatures between −78 and 110° C.

The workup is effected by customary methods, for example by extractingthe products with methylene chloride or toluene from the water-dilutedreaction mixture, washing the organic phase with water, drying anddistilling, or so-called “incipient distillation”, i.e. by prolongedheating under reduced pressure to moderately elevated temperatures, inorder to free the product of the last volatile constituents.

A further purification can be effected by chromatography on silica gelwith, for example, hexane:acetone=7:3 as the eluent. The compounds arecharacterized using NMR spectrum, refractive index, melting point, Rf orboiling point. The optical purity is determined by known methods, forexample NMR with addition of chiral shift reagents, or by gaschromatography on columns with chiral carrier material.

The present invention also relates to novel substituted optically activeamino alcohol derivatives of the formula (7)

in which

-   -   X is hydrogen, COR¹¹ or R¹³, where R¹³ is C₁-C₆-alkyl,    -   R¹ is C₁-C₇-alkyl, C₃-C₇-alkenyl or C₂-C₇-alkynyl,    -   R², R¹¹, R¹³ are the same or different and are each C₁-C₆-alkyl        or C₂-C₇-alkenyl,    -   R³-R⁸ are the same or different and are each hydrogen or        C₁-C₆-alkyl, where R² and R³ or R³ and R⁷ or R³ and R⁵ or R⁵ and        R⁷, likewise together with the atoms to which they are bonded,        may also form a 5- or 6-membered monocyclic ring.

This excludes the following substituent combinations a) to f):

-   -   a) X=hydrogen, R²=methyl and R¹=tert-butyl    -   b) X=hydrogen, R¹=ethyl, R⁵=ethyl, R⁶=ethyl    -   c) X, R³, R⁴, R⁷, R⁸=hydrogen, R¹, R⁵, R⁶=ethyl, R²=methyl    -   d) X, R³, R⁴, R⁸=hydrogen, R¹, R², R⁵, R⁶=ethyl, R⁷=methyl    -   e) X, R³, R⁴, R⁷, R⁸=hydrogen, R¹, R², R⁵, R⁶=ethyl    -   f) X, R³, R⁴, R⁷, R⁸=hydrogen, R¹, R⁵, R⁶=ethyl, R²=n-propyl.

The compounds of the formula (7) are obtained

-   -   a) when the chiral α,ω-amino alcohols, known per se or        preparable by known processes (cf., for example, B. Cesare        Ferri, Reaktionen der org. Synthese, Georg Thieme Verlag        Stuttgart, 1978, p. 211 ff. or 496-497), of the formula

in which

R² to R⁸ are each defined as specified in formula (7) are first reactedwith carbonic acid derivatives, known per se, of the formula (9)

where R¹ is defined as specified in formula 7 and Y is halogen or aleaving group customary in amidation reactions, preferably an activatingester radical or a group

optionally in the presence of a diluent and optionally with addition ofa base.

For the preparation of compounds of the general formula (7) in which Xis other than hydrogen, in a second reaction step, optionally afterisolation of the intermediate with a free OH group, the furtheracylation/alkylation is then effected with carbonyl chlorides, known perse, of the formula (4)

R¹¹COCl   (4)

to prepare compounds of the formula (7) where X═COR¹¹, or alkyl halidesof the formula (6)

R¹³—Y   (6)

to prepare compounds of the formula (1) where X═R¹³, where Y in theformulae (4), (6) is chlorine, bromine or iodine, preferably bromine oriodine, and R¹¹ and R¹³ are each as defined above, the reactionoptionally being effected in the presence of an acid acceptor, forexample triethylamine or potassium carbonate, or of a base such assodium hydride or butyllithium, optionally using a diluent, for exampletoluene, tetrahydrofuran or acetonitrile, at temperatures between −78and 110° C.

-   -   b) The compounds of the formula (7) are also obtained when the        chiral α,ω-amino alcohols or α,ω-amino ethers, known per se or        preparable by known processes, of the formula (12)

in which

R³ to R⁸ are each defined as specified in formula (7) and where X′ ishydrogen or R¹³, where R¹³ is optionally substituted alkyl or alkenyl,are first reacted with chiral chlorocarbonic esters, known per se, ofthe formula (3), optionally in the presence of an acid acceptor, forexample triethylamine or potassium carbonate, and optionally using adiluent, for example toluene, CH₂Cl₂, tetrahydrofuran or acetonitrile,preferably at temperatures between −40 and 110° C.

In a second reaction step, for the preparation of compounds of theformula (7) in which X is not R¹³ or hydrogen, optionally afterisolation of the intermediate with a free OH group, the furtheracylation is effected with carbonyl chlorides, known per se, of theformula (4) to prepare compounds of the formula (7) where X═COR¹¹, whereR¹¹ and R¹² in the formula (4) are each defined as specified above,optionally in the presence of an acid acceptor, for exampletriethylamine or potassium carbonate, optionally using a diluent, forexample toluene, tetrahydrofuran or acetonitrile, at temperaturesbetween −78 and 110° C.

In a third reaction, optionally after isolation of the intermediate witha free NH group, the further N-alkylation is then effected with alkylhalides of the formula (11)

R²—Y′  (11)

to prepare compounds of the formula (7) where Y′ is chlorine, bromine oriodine, preferably bromine or iodine, and R² is defined as specifiedabove, optionally in the presence of a base, for example sodium hydrideor butyllithium, optionally using a diluent, for example toluene ortetrahydrofuran, at temperatures between −78 and 110° C.

The workup is effected by customary methods, for example by extractionof the products with methylene chloride or toluene from thewater-diluted reaction mixture, washing of the organic phase with water,drying and distilling, or so-called “incipient distillation”, i.e. byprolonged heating under reduced pressure to moderately elevatedtemperatures, in order to free it from the last volatile constituents.

Further purification can be effected by chromatography on silica gelwith, for example, hexane:acetone=7:3 as the eluent.

The novel substituted optically active α,ω-amino alcohol derivatives ofthe general formula (7) are notable for strong insect- andmite-repellent action. They can also be used in synergistic mixtureswith other repellents.

The radicals specified in the formula (7) are preferably each defined asfollows:

Examples of the alkyl group in the R¹ to R¹³ radicals include: methyl,ethyl, n- and i-propyl, n-, s- and t-butyl, n-pentyl and n-hexyl.

Examples of alkenyl include: 2-propenyl, 2-butenyl and 3-butynyl.

Particular preference is given to compounds of the general formula (7)in which

-   -   X is hydrogen or R¹³, where R¹³ is C₁-C₆-alkyl,    -   R¹ is C₁-C₇-alkyl or C₃-C₇-alkenyl,    -   R⁴ to R⁸ are the same or different and are each hydrogen or        C₁-C₆-alkyl,    -   R² and R³ together with the atoms to which they are bonded, may        also form a 5- or 6-membered monocyclic ring.

Additionally preferred are compounds of the formula (7) in which R¹ isC₁-C₇-alkyl, C₃-C₇-alkenyl or C₂-C₇-alkynyl, X is hydrogen, COR¹¹ orR¹³, R² and R¹¹ are the same or different and are each C₁-C₆-alkyl, R³to R⁸ are the same or different and are each hydrogen or C₁-C₆-alkyl,R¹³ is C₁-C₆-alkyl,

excluding the following substituent combinations a) to f):

-   -   a) X=hydrogen, R²=methyl and R′=tert-butyl,    -   b) X=hydrogen, R′=ethyl, R⁵=ethyl, R⁶=ethyl    -   c) X, R³, R⁴, R⁷, R⁸=hydrogen, R¹, R⁵, R⁶=ethyl, R²=methyl    -   d) X, R³, R⁴, R⁸=hydrogen, R¹, R², R⁵, R⁶=ethyl, R⁷=methyl    -   e) X, R³, R⁴, R⁷, R⁸=hydrogen, R¹, R², R⁵, R⁶=ethyl    -   f) X, R³, R⁴, R⁷, R⁸=hydrogen, R¹, R⁵, R⁶=ethyl, R²=n-propyl.

When, for example, S-(+)-2-(2-hydroxyethyl)piperidine and sec-butyl(R)-(−)-chloroformate are used as starting materials, the reaction ofthese compounds can be outlined by the following formula scheme:

Particular preference is given to enantiomerically enriched substitutedα,ω-amino alcohol derivatives of the formula (7), characterized in thatthey are from the group of1-[(S)-sec-butyloxycarbonyl]-2-(S)-(2-hydroxyethyl)piperidine,1-[(R)-sec-butyloxycarbonyl]-2-(R)-(+)-(2-hydroxyethyl)piperidine,1-[(S)-sec-butoxycarbonyl]-2-(R)-(+)-(2-hydroxyethyl)piperidine or1-[(R)-sec-butyloxycarbonyl)-2-(S)-(+)-(2-hydroxyethyl)piperidine.Particular preference is given to1-[(R)-sec-butyloxycarbonyl)-2-(S)-(2-hydroxyethyl)piperidine and1-[(R)-sec-butyloxycarbonyl)-2-(R)-(2-hydroxyethyl)piperidine.

The action of the repellents of the general formula (1 or 7) islong-lasting. They can therefore be used with good success forrepellency of harmful or annoying, sucking and biting insects and mites.

The sucking insects include essentially the mosquitoes (e.g. Aedes,Culex and Anopheles species), sandflies (Phlebotoma), biting midges(Culicoides species), blackflies (Simulium species), biting houseflies(e.g. Stomoxys calcitrans), tsetse flies (Glossina species), horseflies(Tabanus, Haematopota and Chrysops species), common houseflies (e.g.Muca domestica and Fannia canicularis), fleshflies (e.g. Sarcophagacarnaria), flies which cause myiasis (e.g. Lucilia couprina, Chrysomyiachloropyga, Hypoderma bovis, Hypoderma lineatum, Dermatobia hominis,Oestrus ovis, Gasterophilus intestinalis, Cochliomyia hominovorax), bugs(e.g. Cimex lectularius, Rhodnius prolixus, Triatoma infestans), lice(e.g. Pediculus humanus, Haematipinus suis, Damalina ovis), louse flies(e.g. Melaphagus orinus), fleas (e.g. Pulex irritans, Cthenocephalidescanis, Xenopsylla cheopsis) and sandfleas (e.g. Dermatophiluspenetrans).

The biting insects include essentially cockroaches (e.g. Blattelagermanica, Periplaneta americana, Blatta orientalis, Supellasupellectilium), beetles (e.g. Sitophilus granarius, Tenebrio molitor,Dermestes lardarius, Stegobium paniceum, Anobium punctactum, Hylotrupesbajulus), termites (e.g. Reticulitermes lucifugus) and ants (e.g. Lasiusniger).

The mites include ticks (e.g. Ornithodorus Moubata, Ixodes ricinus,Boophilus microplus, Amblyomma hebreum), and mites in the narrower sense(e.g. Sarcoptes scabiei, Dermanyssus gallinae).

The present invention thus relates to the preparation and use ofoptically active substituted α,ω-amino alcohol derivatives of thegeneral formula 1 for insect and mite repellency.

The invention further relates to insect and mite repellents,characterized by the content of at least one substituted α,ω-aminoalcohol derivative of the general formula (1) or (7).

The inventive repellents which comprise at least one derivative of theformula (1) or (7) may also comprise further insect repellents. Allrepellents customary in practice are useful here (cf., for example, K.H. Büchel in Chemie der Pflanzenschutz- und Schädlingsbekämpfungsmittel;editor: R. Wegler, vol. 1, Springer Verlag Berlin, Heidelberg, New York,1970, p. 487 ff.).

In the case of repellent combinations, preference is given to using thesubstituted α,ω-amino alcohol derivatives of the general formula 1together with repellent carboxamides, 1,3-alkanediols and carboxylicesters. Specific examples include: N,N-diethyl-3-methylbenzamide (DEET),2-ethylhexane-1,3-diol (Rutgers 612) and dimethyl phthalate.

The substituted α,ω-amino alcohol derivatives usable in accordance withthe invention are characterized by the general formula (1).

Preference is given to using enantiomerically enriched compounds of thegeneral formula (1) as repellents, in which

-   -   X is hydrogen or R¹³, where R¹³ is C₁-C₆-alkyl,    -   R¹ is linear or branched C₁-C₇-alkyl or C₃-C₇-alkenyl,    -   R⁴-R⁸ are the same or different and are each hydrogen or        C₁-C₆-alkyl,    -   R² and R³ together with the atoms to which they are bonded, form        a 5- or 6-membered monocyclic ring.

Preference is further given to compounds in which R¹ is C₁-C₇-alkyl orC₃-C₇-alkenyl, X is COR¹¹ or R¹³, R² and R¹¹ are the same or differentand are each C₁-C₆-alkyl, R³ to R⁸ are the same or different and areeach hydrogen or C₁-C₆-alkyl, and R¹³ is C₁-C₆-alkyl.

More particularly, the repellents used are the compounds of the generalformula (1) in which R¹ is C₁-C₄-alkyl, R², R¹¹ and R¹³ are the same ordifferent and are each C₁-C₆-alkyl, R³-R⁸ are hydrogens and X ishydrogen, COR¹¹ or R¹³, where R¹¹ and R¹³ are each as defined above.

The repellents used are additionally most preferably compounds of thegeneral formula (1) in which R¹ is C₃-C₄-alkyl, R² and R³ together withthe atoms to which they are bonded form a 6-membered ring, R⁴ to R⁸ areeach hydrogen and X is hydrogen or R¹³, where R¹³ is C₁-C₄-alkyl.

The inventive active ingredients, which can be used undiluted orpreferably diluted, can be converted to the formulations customary forrepellents. They can be used in all administration forms customary incosmetics, for example in the form of solutions, emulsions, gels,ointments, pastes, creams, powders, sticks, sprays or aerosols fromspray cans.

For use in the noncosmetic sector, the active ingredients can beincorporated, for example, into granules, oil sprays or slow-releaseformulations.

The formulations are produced in a known manner by mixing or dilutingthe inventive active ingredients with solvents (e.g. xylene,chlorobenzenes, paraffins, methanol, ethanol, isopropanol, water),carriers (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fattyalcohol ethers, alkylsulfonates, arylsulfonates) and dispersants (e.g.lignin, sulfite waste liquors, methylcellulose).

The inventive active ingredients can be used in the formulations mixedwith one another or else in mixtures with other known active ingredients(e.g. sunscreens). The formulations contain generally between 0.1 and95% by weight of active ingredient, preferably between 0.5 and 90% byweight.

For protection against blood-sucking insects or ticks, the inventiveactive ingredients are either applied to the human or animal skin, oritems of clothing or other objects are treated with them. The inventiveactive ingredients are also suitable as an additive of impregnatingagents for, for example, textile webs, items of clothing, packagingmaterials, and as an additive to polishes, cleaners and window cleaners.

The examples of the formulations and the use of the inventive activeingredients which follow serve to further illustrate the invention.

EXAMPLES A) Formulation Examples Formulation Example 1

A repellent in the form of a lotion for application to the skin isproduced by mixing parts of an inventive active ingredient, 1.5 parts ofperfume and 78.5 parts of isopropanol. Isopropanol can be replaced byethanol.

Formulation Example 2

A repellent in the form of an aerosol for spraying onto the skin isproduced by formulating 50% active ingredient solution consisting of 30parts of one of the inventive active ingredients, 1.5 parts of perfume,68.5 parts of isopropanol, with 50% Frigen 11/12 (=halogenatedhydrocarbon as a propellant gas) as a spray can preparation. Frigen canbe replaced by dinitrogen monoxide or butane.

Formulation Example 3

Another spray can preparation is composed of 40% active ingredientsolution, consisting of 20 parts of one of the inventive activeingredients, 1 part of perfume, 79 parts of isopropanol and 60%propane/butane (ratio 15:85).

Individual formulations were produced corresponding to formulationexamples 1, 2 and 3 using the following active ingredients: compoundsaccording to preparation examples Nos. 1, 2, 3, 4.

Repellent Tests:

A) Repellent Test on a Guinea Pig

Test Animal: Aedes aegypti (Imagines)

Solvent: ethanol (99.8%)

3 parts by weight of active ingredient are taken up in 100 parts byvolume of solvent

A guinea pig whose back has been shaved in an area of 50 cm² isaccommodated in a box such that only the shaved area is accessible tothe mosquitoes. After treating the area with 0.4 ml of active ingredientsolution, the guinea pig, after evaporation of the solvent, is placed inits box into a cage measuring 60×60×60 cm, which contains mosquitoes ofboth genders fed only with sugared water.

It is observed for 10 minutes how many mosquitoes bite the guinea pig.Subsequently, it is removed and the test is repeated after 1 hour. Theexperiment is performed for a maximum of 9 hours or until the effectceases.

Table A Repellent test on a guinea pig (Aedes aegypti) Protection  Preparation Formula time in h 1-[S]-sec- butyloxycarbonyl]-2-(S)-2-hydroxyethyl)piperidine

3.9 1-[R]-sec- butyloxycarbonyl]-2-(R)- (2-hydroxyethyl)piperidine

4.4 1-[(R)-sec- butyloxycarbonyl]-2-(S)- (2-hydroxyethyl) piperidine

3.4 1-[-(S-sec- butyloxycarbonyl]-2-(R)- 2-hydroxyethyl)piperidine

4.9

B) Repellent Effectiveness of Formulations for Use Against Mosquitoes onthe Human Arm:

The insects, as an actively biting population (approx. 1000 mosquitoesof both genders), are kept in cages (length 90 cm, width 30 cm, height40 cm, side walls made of gauze) which have two light fabric gates onthe front side. The insects have been fed exclusively with sugared water(10% Dextropur). The age of the insects is at least 7 days; the numberof insects is made up twice per week by 3-day old fully grown insects.

The biting activities are checked every hour continuously during thetest period by exposing an untreated arm to the insects (an additionalinternal product standard is used by a selected volunteer).

The low electrical illumination of the cage is active from 6 am to 6 pm,with light from 6 pm to 6 am. The temperature is 25-27° C.; the relativeair humidity is 50-70%.

The lower arms of the test subjects are washed with unperfumed soap,rinsed with water, then rinsed with a solution of 70% ethanol and 30%water, and dried with a towel.

90 cm² of each lower arm of a test subject is rubbed uniformly with 150μl (or 150 mg) of the test product. As soon as the formulation is dry(after approx. 5 minutes), a sleeve with an opening of 3.1-8 cm (25 cm²)is bound around the arm such that the opening is completely over thetreated surface. The corners of the opening of the sleeve have likewisebeen rubbed with the test material (2000) in a width of 1 cm in order toprevent bites at the corners. The area above the sleeve has beenprotected with a towel through which the mosquitoes cannot penetrate.Hands are protected with latex gloves.

Both arms are introduced into the cage through the fabric gate, and thenumber of bites (and landings, if necessary) per arm is noted within a3-minute test period. The test is repeated every hour for up to 8 hours,or ended beforehand if the effect ceases (3 or more bites within 3minutes or during 2 successive test sequences). Each test consists ofthree to 5 test subjects.

Table B reports the increase in the protection time of the inventiveenantiomerically enriched compounds compared to the racemic mixture.

Table B Repellent test against mosquitoes on the human lower armIncrease in the Preparation Formula protection time* in % 1-[S]-sec-butyloxycarbonyl]-2-(S)- 2-hydroxyethyl)piperidine

 0 1-[(R)-sec- butyloxycarbonyl]-2- (R)-(2- hydroxyethyl)piperidine

 3 1-[(R)-sec- butyloxycarbonyl]-2- (S)-(2- hydroxyethyl)piperidine

12 1-[(S)-sec- butyloxycarbonyl]-2- (R)-2- hydroxyethyl)piperidine

 0 *standard racemic mixture

B) Preparation Examples Example 11-[(S)-sec-butyloxycarbonyl]-2-(S)-(2-hydroxyethyl)piperidine (a)2-(S)-(2-hydroxyethyl)piperidine camphorsulfonate

-   -   A solution of 25.5 g of dl-2-(2-hydroxyethyl)piperidine in 50 ml        of ethanol was slowly added dropwise at 0-10° C. to a solution        of 64 g of (1S)-(+)-camphor-10-sulfonic acid monohydrate in 80        ml of ethanol. The mixture was left to stand overnight and then        25 ml of ethanol were distilled off. After cooling,        precipitation was effected with 600 ml of diethyl ether. After        filtration with suction and drying in a drying cabinet, 86 g of        almost colorless solid of melting point 125-130° C. (lit.        118-120) were obtained. The solid is then dissolved at 65° C. in        87 ml of ethanol to give an almost clear solution, and        hot-filtered. The mother liquor was allowed to come to room        temperature overnight and was filtered with suction. The        resulting solid, 27 g with a melting point of 137-145° C., was        dissolved again in 60 ml of ethanol at 70° C. The mixture was        admixed with diethyl ether until it became slightly cloudy and        was warmed to room temperature overnight. After the precipitate        had been filtered off with suction, 13.7 g of KBR9527-1 with a        melting point of 158-160° C. were obtained. Redissolution in 30        ml of ethanol at 70° C. and admixing with diethyl ether until        slight cloudiness led, after filtration with suction and drying,        to 9 g of d-2-(2-hydroxyethyl)piperidine d-10-camphorsulfonate        with a melting point of 168° C. (literature: 168° C., S. M.        Kupchan et al. J. Am. Chem. Soc. 82 (1960) 2616).

(b) Determination of the absolute configuration by x-ray structureanalysis

-   -   Several crystals of the material obtained above were        crystallized by slow evaporation of a saturated acetone        solution. A solution with the structure corresponding to        proposal (1) was obtained by means of a monoclinic cell using        the chiral residual group P2₁. The final configuration is fixed        by S(C2); R(C5), R(C11) based on a Flack parameter of −0.03 with        a standard deviation of 0.04. Expected measurements were 0 for        correct and +1 for mirror-image structures.    -   The Ortep plot and the exact data are shown in FIG. 1

(c) 1-[(S)-sec-butyloxycarbonyl]-2-(S)-(2-hydroxyethyl)piperidine

3.6 g (0.0996 mol) of the (+)-camphorsulfonate obtained in 1(a) wereinitially charged in 50 ml of toluene. At 20° C., 50 ml (0.05 mol) of 1Nsodium hydroxide solution were added dropwise with vigorous stirring.After a continued stirring time of 5 minutes, 1.5 g (0.01099 mol) of(S)-(+)-sec-butyl chloroformate are added dropwise at 20° C. Stirring iscontinued for 1 hour and the organic phase is removed, dried overmagnesium sulfate and concentrated fully under reduced pressure.

Yield: 1.95 g (85% of theory) of1-[(S)-sec-butyloxycarbonyl]-2-(S)-(2-hydroxyethyl)piperidine

[α]_(D) ²⁵: −13.2° (CHCl₃)

The other enantiomers were obtained in an analogous manner by thefollowing routes:

1-[(R)-sec-butyloxycarbonyl]-2-(R)-(+)-(2-hydroxyethyl)piperidine

Is from the (−)-camphorsulfonate of 2-(R)-(2-hydroxyethyl)piperidine andR-(−)-sec-butyl chloroformate [α]_(D) ²⁵: +12.6° (CHCl₃)

1-[(S)-sec-butyloxycarbonyl]-2-(R)-(+)-(2-hydroxyethyl)piperidine

From the (−)-camphorsulfonate and (R)-(+)-sec-butyl chloroformate

[α]_(D) ²⁵: +49.6° (CHCl₃)

1-[(R)-sec-butyloxycarbonyl]-2-(S)-(+)-(2-hydroxyethyl)piperidine

From the (+)-camphorsulfonate and (R)-(−)-sec-butyl chloroformate

[α]_(D) ²⁵: −50.6° (CHCl₃)

TABLE 1 Crystal data and structure refining for 2-(S)-(2-hydroxyethyl)piperidine camphorsulfonate Identification code Kbr9527g Empirical formula C17 H31 N O5 S Formula weight 361.49 Temperature153(2) K Wavelength 0.71073 Å Crystal system Monocyclic Space group P21Unit cell dimensions a = 8.804040(10) Å α = 90° b = 7.158740(10) Å β =92.1410(10)° c = 14.7546(2) Å γ = 90° Volume 929.27(2) Å³ Z 2 Density(calculated) 1.292 Mg/m³ Absorption coefficient 0.200 mm⁻¹ F(000) 392Crystal size 0.30 × 0.30 × 0.30 mm³ Theta range for data collection 2.31to 31.40° Index ranges −12 ≦ h ≦ 12, −10 ≦ k ≦ 10, −21 ≦ 1 ≦ 21Reflections collected 14189 Independent reflections 5895 [R(int) =0.0487] Completeness to theta = 31.49° 96.4% Absorption correctionSADABS (Bruker-AXS) Refinement method Full-matrix least-squares on F²Data/restraints/parameters 5895/1/341 Goodness-of-fit on F² 1.033 FinalR indices [I > 2 sigma (I)] R1 - 0.0382, wR2 = 0.0960 R indices (alldata) R1 = 0.0391, wR2 = 0.0968 Absolute structure parameter −0.03 (4)Largest diff. peak and hole 0.255 and −0.343 e · Å⁻³

TABLE 2 Bond lengths [Å] and angles [°] for 2-(S)-(2-hydroxyethyl)piperidine camphorsulfonate S(1)-O(1) 1.4567(8)C(2)-O(8) 1.8649(14) C(8)-C(9) 1.5276(15) S(1)-O(2) 1.4603(9) C(3)-O(4)1.2114(16) C(11)-C(12) 1.5223(16) S(1)-O(3) 1.4660(9) C(3)-C(4)1.5247(17) C(11)-C(16) 1.5255(16) S(1)-C(1) 1.7802(11) C(4)-C(5)1.5385(17) C(12)-C(13)  1.532(2) N(1)-C(15) 1.4962(15) C(5)-C(6)1.5371(16) C(13)-C(14)  1.520(2) N(1)-C(11) 1.5022(13) C(5)-C(8)1.5559(15) C(14)-C(15) 1.5214(16) C(1)-C(3) 1.8272(14) C(5)-C(17)1.4268(18) C(15)-C(17) 1.5246(19) C(2)-C(3) 1.5335(15) C(6)-C(7)1.5501(16) C(2)-C(7) 1.5600(14) C(8)-C(10) 1.5239(16) O(6)-S(6)-O(3)113.15(6) C(6)-C(5)-C(8) 102.28(8) O(1)-S(1)-O(3) 112.21(5)C(4)-C(5)-C(8) 103.09(9) O(2)-S(1)-O(3) 112.18(6) C(5)-C(6)-C(2)103.36(9) O(1)-S(1)-C(1) 108.17(6) C(6)-C(7)-C(2) 103.80(8)O(2)-S(1)-O(1) 106.98(5) C(10)-C(8)-C(9) 107.99(10) O(3)-S(1)-C(1)103.46(6) C(10)-C(8)-C(5) 113.02(9) C(15)-N(1)-C(11) 111.92(8)C(9)-C(8)-C(5) 113.94(10) C(2)-C(1)-S(1) 119.04(7) C(10)-C(8)-C(2)114.79(8) C(1)-C(2)-C(1) 110.87(8) C(9)-C(8)-C(2) 113.02(9)C(1)-C(2)-C(7) 119.03(8) C(5)-C(8)-C(2) 93.76(8) C(3)-C(2)-C(7)102.20(8) N(1)-C(11)-C(12) 108.10(9) C(1)-C(2)-C(8) 119.24(8)N(1)-C(11)-C(16) 111.38(9) C(3)-C(2)-C(8) 100.45(8) C(12)-C(11)-C(16)112.09(10) C(7)-C(2)-C(8) 102.27(8) C(11)-C(12)-C(13) 111.83(10)O(4)-C(3)-C(2) 126.50(11) C(14)-C(13)-C(12) 110.90(11) O(4)-C(3)-C(2)126.29(11) C(13)-C(14)-C(15) 110.55(10) C(4)-C(3)-C(2) 107.21(9)N(1)-C(15)-C(14) 109.71(10) C(3)-C(4)-C(5) 101.19(9) C(17)-C(16)-C(11)115.38(10) C(6)-C(5)-C(4) 106.16(10) O(5)-C(17)-C(16) 111.81(11)

TABLE 3 Torsion angles [°] for 2-(S)-(2-hydroxyethyl)piperidinecamphorsulfonate O(1)-S(1)-C(1)-C(2) −62.53(10)  C(6)-C(5)-C(8)-C(9)172.04(10)  O(2)-S(1)-C(1)-C(2) 59.67(10) C(4)-C(5)-C(8)-C(9) 61.78(12)O(1)-S(1)-C(1)-C(2) 178.29(9)   C(6)-C(5)-C(8)-C(2) 54.78(10)S(1)-C(1)-C(2)-C(3) −138.70(8)   C(4)-C(5)-C(8)-C(2) −55.48(10) S(1)-C(1)-C(2)-C(7) −20.66(13)  C(1)-C(2)-C(8)-C(10) −68.98(12) S(1)-C(1)-C(2)-C(8) 105.45(10)  C(3)-C(2)-C(8)-C(10) 169.78(9) C(1)-C(2)-C(3)-O(4) 21.07(16) C(7)-C(2)-C(8)-C(10) 64.72(11)C(7)-C(2)-C(3)-O(4) −106.79(13)  C(1)-C(2)-C(8)-C(9) 55.48(13)C(8)-C(2)-C(3)-C(4) 148.08(13)  C(3)-C(2)-C(8)-C(9) −65.76(11) C(1)-C(2)-C(3)-C(4) −159.91(9)   C(7)-C(2)-C(8)-C(9) −170.82(10) C(7)-C(2)-C(3)-C(4) 72.23(10) C(1)-C(2)-C(8)-C(6) 173.50(9)  C(8)-C(2)-C(3)-C(4) −32.90(11)  C(3)-C(2)-C(8)-C(5) 52.26(9) C(4)-C(3)-C(4)-C(5) 171.24(13)  C(7)-C(2)-C(8)-C(5) −52.80(9)  C(2)-C(3)-C(4)-C(5) −1.78(12) C(15)-N(1)-C(11)-C(12) 60.30(11)C(3)-C(4)-C(5)-C(6) −71.31(11)  C(15)-N(1)-C(11)- −176.14(9)   C(3)-C(4)-C(5)-C(8) 36.49(11) N(1)-C(11)-C(12)-C(13) −56.57(13) C(4)-C(5)-C(6)-C(7) 71.54(11) C(16)-C(11)-C(12)-C(13) −179.70(10)  C(8)-C(5)-C(6)-C(7) −36.40(12)  C(11)-C(12)-C(13)-C(14) 54.84(15)C(5)-C(6)-C(7)-C(2)  1.97(12) C(12)-C(13)-C(14)-C(15) −54.06(16) C(1)-C(2)-C(7)-C(6) 166.57(10)  C(11)-N(1)-C(15)-C(14) −61.19(11) C(2)-C(2)-C(7)-C(6) 70.94(10) C(13)-C(14)-C(15)-N(1) 56.87(14)C(8)-C(2)-C(7)-C(6) 32.74(11) N(1)-C(11)-C(16)-C(17) 62.39(13)C(6)-C(5)-C(8)-C(10) 64.20(12) C(12)-C(11)-C(16)-C(17) 176.54(10) C(4)-C(5)-C(8)-C(10) −174.46(9)   C(11)-C(16)-C(17)-O(5) 55.73(14)

FIG. 1: Ortep plot (50%) of 2-(S)-(2-hydroxyethyl)piperidiniumα-camphorsulfonate with numbering of the non-hydrogen atoms

1. An insect and mite repellent, characterized by a content of at leastone substituted enantiomerically enriched α,ω-amino alcohol derivativeof the formula (1)

in which X is hydrogen, COR¹¹ or R¹³, where R¹³ is C₁-C₆-alkyl, R¹ isC₁-C₇-alkyl, C₃-C₇-alkenyl or C₂-C₇-alkynyl, R², R¹¹, R¹³ are the sameor different and are each C₁-C₆-alkyl or C₂-C₇-alkenyl, R³ to R⁸ are thesame or different and are each hydrogen or C₁-C₆-alkyl, where R² and R³or R³ and R⁷ or R³ and R⁵ or R⁵ and R⁷, together with the atoms to whichthey are bonded, may also form a 5- or 6-membered monocyclic ring.
 2. Anenantiomerically enriched substituted α,ω-amino alcohol derivative ofthe formula (7)

in which X is hydrogen, COR¹¹ or R¹³, where R¹³ is C₁-C₆-alkyl, R¹ isC₁-C₇-alkyl, C₃-C₇-alkenyl or C₂-C₇-alkynyl, R², R¹¹, R¹³ are the sameor different and are each C₁-C₆-alkyl or C₂-C₇-alkenyl, R³ to R⁸ are thesame or different and are each hydrogen or C₁-C₆-alkyl, where R² and R³or R³ and R⁷ or R³ and R⁵ or R⁵ and R⁷, likewise together with the atomsto which they are bonded, may also form a 5- or 6-membered monocyclicring, excluding the following substituent combinations a) to f): a)X=hydrogen, R²=methyl and R¹=tert-butyl b) X=hydrogen, R¹=ethyl,R⁵=ethyl, R⁶=ethyl c) X, R³, R⁴, R⁷, R⁸=hydrogen, R¹, R⁵, R⁶=ethyl,R²=methyl d) X, R³, R⁴, R⁸=hydrogen, R¹, R², R⁵, R⁶=ethyl, R⁷=methyl e)X, R³, R⁴, R⁷, R⁸=hydrogen, R¹, R², R⁵, R⁶=ethyl f) X, R³, R⁴, R⁷,R⁸=hydrogen, R¹, R⁵, R⁶=ethyl, R²=n-propyl.
 3. An enantiomericallyenriched substituted α,ω-amino alcohol derivative of the formula (7) asclaimed in claim 2 in which X is hydrogen or R¹³, where R¹³ isC₁-C₆-alkyl, R¹ is C₁-C₇-alkyl or C₃-C₇-alkenyl, R⁴ to R⁸ are the sameor different and are each hydrogen or C₁-C₆-alkyl, R² and R³ togetherwith the atoms to which they are bonded, may also form a 5- or6-membered monocyclic ring.
 4. An enantiomerically enriched substitutedα,ω-amino alcohol derivative of the formula (7) as claimed in claim 2 inwhich R¹ is C₁-C₇-alkyl, C₃-C₇-alkenyl or C₂-C₇-alkynyl, X is hydrogen,COR¹¹ or R¹³, R² and R¹¹ are the same or different and are eachC₁-C₆-alkyl, R³ to R⁸ are the same or different and are each hydrogen orC₁-C₆-alkyl, R¹³ is C₁-C₆-alkyl, excluding the following substituentcombinations a) to f): a) X=hydrogen, R²=methyl and R¹=tert-butyl, b)X=hydrogen, R¹=ethyl, R⁵=ethyl, R⁶=ethyl c) X, R³, R⁴, R⁷, R⁸=hydrogen,R¹, R⁵, R⁶=ethyl, R²=methyl d) X, R³, R⁴, R⁸=hydrogen, R¹, R², R⁵,R⁶=ethyl, R⁷=methyl e) X, R³, R⁴, R⁷, R⁸=hydrogen, R¹, R², R⁵, R⁶=ethylf) X, R³, R⁴, R⁷, R⁸=hydrogen, R¹, R⁵, R⁶=ethyl, R²=n-propyl.
 5. Anenantiomerically enriched substituted α,ω-amino alcohol derivative ofthe formula (7), characterized in that it is from the group of1-[(R)-sec-butyloxycarbonyl]-2-(+)-(2-hydroxyethyl)piperidine,1-[(R)-sec-butyloxycarbonyl]-2-(R)-(+)-(2-hydroxyethyl)piperidine,1-[(S)-sec-butyloxycarbonyl]-2-(R)-(+)-(2-hydroxyethyl)piperidine or1-[(R)-sec-butyloxycarbonyl]-2-(R)-(+)-2-hydroxyethyl)piperdine.
 6. Aprocess for preparing enantiomerically enriched substituted α,ω-aminoalcohol derivatives of the general formula (7)

in which X is hydrogen, COR¹¹ or R¹³, where R¹³ is C₁-C₆-alkyl, R¹ isC₁-C₇-alkyl, C₃-C₇-alkenyl or C₂-C₇-alkynyl, R², R¹¹, R¹³ are the sameor different and are each C₁-C₆-alkyl or C₂-C₇-alkenyl, R³ to R⁸ are thesame or different and are each hydrogen or C₁-C₆-alkyl, where R² and R³or R³ and R⁷ or R³ and R⁵ or R⁵ and R⁷, likewise together with the atomsto which they are bonded, may also form a 5- or 6-membered monocyclicring, excluding the following substituent combinations a) to f): a)X=hydrogen, R²=methyl and R¹=tert-butyl b) X=hydrogen, R¹=ethyl,R⁵=ethyl, R⁶=ethyl c) X, R³, R⁴, R⁷, R⁸=hydrogen, R¹, R⁵, R⁶=ethyl,R²=methyl d) X, R³, R⁴, R⁸=hydrogen, R¹, R², R⁵, R⁶=ethyl, R⁷=methyl e)X, R³, R⁴, R⁷, R⁸=hydrogen, R¹, R², R⁵, R⁶=ethyl f) X, R³, R⁴, R⁷,R⁸=hydrogen, R¹, R⁵, R⁶=ethyl, R²=n-propyl, characterized in that a)enantiomerically enriched am-amino alcohol derivatives of the formula(8)

in which R² to R⁸ are each defined as specified in formula (7) arereacted with chiral carbonic acid derivatives of the formula (9)

where R¹ is as defined in formula (7) and Y is halogen or a leavinggroup customary in amidation reactions, optionally in the presence of adiluent and optionally with addition of a base, the resulting compoundsof the formula (7) in which X is hydrogen are optionally isolated andare optionally reacted, to obtain compounds of the formula (7) in whichX is COR¹¹, with carbonyl chlorides of the formula (4)R¹¹—COCl   (4) or optionally, to obtain compounds of the formula (7) inwhich X is R¹³, with alkyl halides of the formula (6)R¹³—Y   (6) in which Y is chlorine, bromine or iodine, b) or chiralα,ω-amino alcohol derivatives or chiral α,ω-amino ethers of the formula(12)

in which R³ to R⁸ are each defined as specified in formula (7), and inwhich X′ is hydrogen or R¹³, where R¹³ is C₁-C₆-alkyl, are first reactedwith chiral chlorocarbonic esters of the formula (9)

in which R¹ is a chiral radical defined as specified in formula (7),optionally in the presence of an acid acceptor and optionally using adiluent, then, in a second reaction step, optionally after isolating theintermediate with a free OH group (X′═H), to prepare compounds of theformula (7) where X═COR¹¹ where R¹¹ is as defined above, with carbonylchlorides of the formula (4)R¹¹COCl   (4) and, after optional isolation of the intermediate with afree NH group, also with a compound of the formula (11)R²—Y′  (12) in which R² is defined as specified above and Y′ ischlorine, bromine or iodine, optionally in the presence of a base andoptionally using a diluent.
 7. A method for controlling insects andmites, characterized in that enantiomerically enriched substitutedα,ω-amino alcohol derivatives of the formula (1) or (7) are allowed toact on insects and/or mites and/or their habitat.
 8. The use ofenantiomerically enriched substituted α,ω-amino alcohol derivatives ofthe formula (1) or (7) for control of insects and/or mites.
 9. A processfor producing insect and mite repellents, characterized in thatenantiomerically enriched substituted α,ω-amino alcohol derivatives ofthe formula (1) or (7) are mixed with extenders and/or surfactants.